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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 8 2916-2920
Copyright © 1998 by The Endocrine Society

Original Studies

Corticotropin-Releasing Hormone Directly and Preferentially Stimulates Dehydroepiandrosterone Sulfate Secretion by Human Fetal Adrenal Cortical Cells1

Roger Smith, Sam Mesiano, Eng-Cheng Chan, Shane Brown and Robert B. Jaffe

Maternal Health Research Centre (R.S., E.-C.C.), John Hunter Hospital, Newcastle, NSW 2310, Australia; Reproductive Endocrinology Center (S.M., R.B.J.), Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California 94143; and Department of Endocrinology (S.B.), Prince of Wales Hospital, High Street, Randwick, NSW 2031, Australia

Address all correspondence and requests for reprints to: Professor Roger Smith, Maternal Health Research Centre, Endocrine Unit, John Hunter Hospital, Locked Bag 1, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia, or to Sam Messiano, Maternal Health Research Centre, John Hunter Hospital, Newcastle, NSW 2310, Australia.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Estrogens produced by the placenta play a pivotal role in the endocrine control of pregnancy and induce many of the key changes involved in parturition. The placentae of humans and higher primates use the C19 androgen dehydroepiandrosterone sulfate (DHEA-S) supplied by the fetal adrenals as the principal substrate for estrogen synthesis. Thus, secretion of androgens by the fetal adrenals may be central to the process of primate parturition. The timing of human parturition also is correlated with placental CRH concentrations in the maternal circulation. Because the mechanisms that regulate DHEA-S production by the fetal adrenals are incompletely understood, we examined whether there is a functional relationship between CRH and steroid production by human fetal adrenal cortical cells. Using Northern blot analysis, we detected messenger RNA transcripts (2.7 kb) encoding the type-1 CRH receptor in total RNA extracted from midgestation human fetal adrenals, suggesting that the fetal adrenal cortex may be directly responsive to CRH. To test this, primary cultures of human fetal adrenal cortical cells were exposed to human CRH. Human CRH increased DHEA-S production by cultured human fetal adrenal cortical cells in a dose-dependent fashion, with an ED50 of 10–100 pmol/L. Human CRH was as effective as ACTH at stimulating DHEA-S production; however, it was 70% less potent than ACTH at stimulating cortisol production, indicating that its actions were preferentially directed toward increasing DHEA-S synthesis. Consistent with this thesis, we found that CRH increased abundance of messenger RNA encoding cytochrome P450 cholesterol side-chain cleavage and 17{alpha}-hydroxylase/17,20 lyase but not 3ß-hydroxysteroid dehydrogenase in adrenal cells. CRH did not alter cell number, indicating that it is not mitogenic for fetal adrenal cortical cells. These data demonstrate a direct functional interaction between CRH and the fetal adrenal. Therefore, placental CRH production, which rises exponentially during human pregnancy, may play a key role in promoting DHEA-S production by the fetal adrenals, which could lead to increasing placental estrogen synthesis and contribute to the process of parturition in humans.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE PHYSIOLOGICAL mechanism by which the timing of parturition is coordinated with fetal maturation, so that it occurs when the fetus is sufficiently mature to live outside of the uterus, is a major unsolved problem in reproductive biology. Cortisol produced by the fetal adrenals plays a key role in fetal development by promoting the maturation of organ systems (e.g. lungs, liver, gut) essential for extrauterine life (for review, see Refs. 1, 2). In some species, fetal adrenal cortisol also triggers the onset of parturition (1). However, this seems not to be the case in primates. Instead, it has been proposed that androgens, produced by the fetal adrenals, may play a key role in the regulation of primate parturition (3). Recently, Mecenas et al. (3) found that maternal infusion of the androgen, androstenedione, in the pregnant rhesus monkey leads to preterm parturition indistinguishable from normal birth, suggesting that the rapid rise in fetal adrenal production of the androgenic and estrogenic precursor, dehydroepiandrosterone sulfate (DHEA-S), toward the end of gestation may effect the onset of parturition. In humans and other primates, the fetal adrenal cortices possess a distinct and disproportionately enlarged central compartment, the fetal zone. The fetal zone increases dramatically in size and steroidogenic capacity as gestation advances, to reach a maximum near the time of parturition, after which it rapidly involutes (4, 5). Fetal zone cells preferentially secrete the C19 androgen DHEA and DHEA-S because they have abundant quantities of cytochrome P450 cholesterol side chain cleavage (P450scc) and P450 17{alpha}-hydroxylase/17,20 lyase (P450c17) but lack 3ß-hydroxysteroid dehydrogenase/{Delta}4–5 isomerase (3ßHSD) (5, 6). The DHEA-S derived from the fetal adrenals is converted by the placenta to estrogens, which reach the maternal circulation and produce many of the key changes associated with parturition, e.g. oxytocin receptor and connexin-43 expression in the myometrium (7, 8).

The mechanism by which DHEA-S production by fetal zone cells is regulated is not fully understood. ACTH secreted by the fetal pituitary, and acting in part via locally produced growth factors, including insulin-like growth factor-II (9) and basic fibroblast growth factor (10), is the principal trophic regulator of fetal zone growth and function. However, the postnatal involution of the fetal zone, despite unchanged exposure to ACTH (11), suggests that the fetal zone also is regulated by a pregnancy specific factor(s). This factor may be CRH. We noted a correlation in the species distribution of the fetal zone and placental production of CRH: both are restricted to primate pregnancies. Furthermore, the relative maximum size of the fetal zone follows the pattern of CRH secretion by the placenta. For example, in the baboon, relative fetal zone size and CRH secretion peak during midgestation (12, 13, 14), whereas in rhesus monkeys (15) and humans (16), both peak near the time of parturition. Furthermore, CRH declines dramatically in the maternal and fetal circulations after parturition, coinciding with the involution of the fetal zone (17). In humans, CRH produced by the placenta may constitute a biological clock that influences the timing of parturition. Based on these observations, we hypothesized that placental CRH may influence fetal adrenal cortical function and therefore provide a mechanism for the coordination of fetal maturation with the timing of parturition. Therefore, in the present study, we conducted experiments to determine whether CRH influences human fetal zone growth and function directly.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell culture

Human fetal adrenal glands were obtained from second-trimester fetuses (16–21 weeks of gestation, estimated by foot length) after elective termination of pregnancy by dilatation and evacuation. The protocol was approved by the Human Research Committee, University of California, San Francisco (UCSF). Primary cultures of human fetal adrenal cells were prepared as previously described (9). Briefly, glands were decapsulated, minced into 1-mm3 pieces, and incubated in 0.1% collagenase (Sigma, St. Louis, MO) at 37 C for 30–40 min, with trituration every 10 min, until cells were completely dispersed. The dispersed cells were centrifuged and resuspended in culture medium, which consisted of a 1:1 (vol:vol) mixture of DMEM H-16/Ham’s F-12 (1:1), supplemented with 10% FCS, 2 mmol/L glutamine, and 50 mg/mL gentamicin (Cell Culture Facility, UCSF). Cells were plated on either 48-well culture dishes at a density of approximately 50,000 cells per well or on 6-cm diameter plates at a density of 500,000 cells per plate. Medium was changed every 48 h. After 4–6 days, ACTH1–24 (0.1 pmol/L to 10 nmol/L final concentration; Organon, West Orange NJ) or CRH (0.1 pmol/L to 10 nmol/L final concentration; Sigma) was added. After a further 24 h, the media were collected, and cells were harvested by trypsinization and either counted, using a particle counter (Coulter Electronics, Hialeah, FL), or processed for RNA analysis.

RIAs

Cortisol and DHEA-S were measured in conditioned medium using specific RIAs that we have described previously (9, 10). Unconjugated cortisol was assayed using a kit purchased from Diagnostic Products Corp., Los Angeles, CA. DHEA-S was assayed using an antiserum specific for DHEA-S purchased from ICN Biomedicals, Inc., Costa Mesa, CA, with charcoal separation of free, from bound, steroid. All assays were validated for use on conditioned medium from fetal adrenal cortical cell cultures, and each had an inter- and intraassay coefficient of variation of less than 10%.

RNA analysis

After exposure to test substances, cells were harvested, and total RNA was extracted using the method of Chomczynski and Sacchi (18). Abundance of messenger RNA (mRNA) for the enzymes P450scc, P450c17, and 3ßHSD was assessed by Northern hybridization analysis of total RNA. Total RNA (5–10 µg) was denatured in 2.2 mol/L formaldehyde and subjected to electrophoresis through a 1.2% agarose gel and then transferred to a Nytran nitrocellulose membrane (Schleicher and Schuelle, Keene, NH). Full-length complementary DNAs (cDNAs) for P450scc and P450c17 were obtained from Dr. W. L. Miller (19, 20), UCSF; and the full-length cDNA for human type-II 3ßHSD was obtained from Dr. F. Labrie (21), Centre de Recherche du Chul, University of Laval, Quebec, Canada. 32P-deoxycycidine triphosphate-labeled cDNA probes were synthesized by random primer extension of full-length cDNAs. Prehybridization was performed in hybridization buffer (Quickhyb Buffer; Stratagene, La Jolla, CA) at 68 C for 15 min. Denatured radiolabeled probe was then added to the membranes and incubated at 68 C for 1 h. Membranes were washed in 2 x saline-sodium citrate (SSC)/0.1% SDS (1 x SSC = 0.15 mol/L NaCl/0.015 mol/L Na citrate) at room temperature for 15 min and then in 0.1 x SSC/1% SDS at 60C for 30 min and subjected to autoradiography at -70 C. Probes were removed by washing the membranes in distilled water at 100 C. Complete removal of probe was confirmed by autoradiography before reprobing. Membranes were hybridized sequentially with the aforementioned cDNA probes, in the order described. Data were normalized relative to the abundance of mRNA-encoding glyceraldehyde phosphate dehydrogenase (GAPDH; American Type Culture Collection, Rockville, MD.).

CRH receptor RNA analyses were performed on total RNA and subjected to electrophoresis on a 1% formaldehyde agarose gel, transferred onto nylon membrane, and hybridized with a 600-base digoxigenin-labeled CRH-R1 riboprobe. The riboprobe used was a pBluescript subclone of a 600-base fragment of the type-1{alpha} CRH receptor corresponding to bases 283–799 of the published sequence (22). Hybridizations were performed at 68 C. Membranes were washed twice with 2 x SSC/0.1% SDS at room temperature for 15 min, followed by 0.1 x SSC/0.1% SDS at 68 C for 15 min, before treatment with antidigoxigenin antibody conjugated to alkaline phosphatase. Hybridized probes were detected using a chemiluminescent substrate, disodium 3-(4-methyoxyspiro{1, 2-dioxetane-3, 2'-(5'-chloro)-tricyclo[3,3,1,13,7]decan}-4-yl) phenyl phosphate or CSPD (Boehringer Mannheim) and subjected to autoradiography.

Statistical analysis

All cortisol and DHEA-S data were normalized for cell number and time of exposure to ACTH and are presented as mean ± SE. All experiments were performed in triplicate wells and repeated in three separate experiments. The effect of CRH on the abundance of mRNAs encoding the steroidogenic enzymes were determined in four separate adrenal dispersions. Statistical analyses were conducted by ANOVA followed by the Newman-Keuls post hoc test for significance between groups. Differences were considered statistically significant when P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A 600-base digoxigenin-labeled riboprobe, transcribed from a CRH receptor type-1 clone, hybridized to fetal adrenal mRNA in Northern analyses, producing a band of 2.7 kb, which was identical in size to RNA from human pituitary tissue (Fig. 1Go).



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  		Figure 1. Northern blot analysis of human pituitary (lane 1) and human fetal adrenal gland (lane 2). Total RNA (10 µg), extracted from the tissues, was separated by electrophoresis, transferred onto a nylon membrane, and probed with a CRH type-1 receptor riboprobe. The analysis was repeated with three different fetal adrenals of similar gestational ages (15–16 weeks), with a similar result as shown in this figure.

 
CRH stimulated cortisol and DHEA-S production by cultured human fetal adrenal cortical cells in a dose-dependent fashion (Fig. 2Go) with an ED50, in both cases, of 10–100 pmol/L. With respect to DHEA-S production, CRH at 1 nmol/L was essentially equipotent to 1 nmol/L ACTH. However, 1 nmol/L CRH was only 30% as potent as 1 nmol/L ACTH at stimulating cortisol production. The steroidogenic effects of CRH on human fetal adrenal cortical cells were therefore preferential for DHEA-S production. There was no significant CRH effect on fetal adrenal cortical cell mitogenic activity, as assessed by DNA quantitation and cell number (data not shown).



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  		Figure 2. Effect of CRH on cortisol and DHEA-S production by primary cultures of human fetal adrenal cortical cells. Cells were cultured in the presence or absence of CRH (0.1 pmol/L to 10 nmol/L) or ACTH (1 nmol/L) for 24 h. Media were then collected and assayed for cortisol and DHEA-S, and cell numbers in each well were measured. Three separate experiments, using adrenal cortical cells from three different midgestation human fetal adrenals, were performed. The data shown here in the left panels are representative of one of these experiments. All other experiments showed the same effects; however, the absolute amounts of cortisol and DHEA-S produced were variable between experiments because of interadrenal variability. The grouped data, therefore, have been pooled and normalized and are shown in the right-hand panels.

 
CRH (1 nmol/L each) increased the abundance of mRNAs encoding P450scc and P450c17 4- to 5-fold in four separate adrenal dispersions (Fig. 3Go) but did not alter the abundance of mRNA encoding 3ßHSD (data not shown). As expected, ACTH markedly increased expression of P450scc, P450c17, and 3ßHSD. Interestingly, CRH was as potent as ACTH at stimulating P450scc expression but was only 20% as potent as ACTH at stimulating P450c17 expression. CRH did not alter ACTH-stimulated steroidogenic enzyme expression, and the two agents were neither additive nor synergystic when added together (Fig. 3Go).



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  		Figure 3. Northern blot analysis of the abundance of mRNAs encoding P450scc, P450c17, and GAPDH in cultured human fetal adrenal cortical cells exposed to CRH. The effects of CRH on steroidogenic enzyme expression were assessed in four separate experiments.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Production of CRH by the placenta only occurs in primate species, and its physiological role has been uncertain (23). Several studies have been performed in old-world monkeys, such as the rhesus, which exhibit a progressive rise in maternal CRH plasma concentrations with gestation (15). In contrast, in the baboon, CRH concentrations rise rapidly, to peak at midgestation but then remain at relatively high levels until parturition (13, 14). In humans, many groups have confirmed the initial findings of Sasaki et al. (24), that maternal plasma concentrations of CRH increase exponentially with gestation. Placental CRH secretion into the maternal plasma has been linked to a biological clock correlated with the length of gestation in humans (16), a shift to the left of the exponential curve is predictive of preterm delivery, whereas a shift to the right is associated with postterm parturition. The mechanism by which placental CRH might precipitate parturition has remained unclear; however, maternal plasma CRH may have direct actions on the myometrium, where CRH receptors have been identified (25). In the quiescent myometrium, CRH receptors are linked to adenylate cyclase efficiently, which may promote relaxation by increasing cAMP; whereas, in the parturient myometrium, CRH-adenylate cyclase uncoupling occurs, potentially leading to a fall in cAMP and an increase in contractility (26). CRH has also been shown to potentiate oxytocin (27) and PGF2{alpha}-induced (28) contractions in the myometrium. Others have suggested that CRH secretion into the fetal circulation may play a role by stimulating fetal pituitary production of ACTH and, consequently, cortisol release from the fetal adrenal (29). This proposal suggests a positive feed-forward loop, because glucocorticoids have been shown to stimulate placental CRH production (29). Our present data suggest that placental CRH preferentially increases DHEA-S production from the fetal zone of the human fetal adrenal gland.

The mechanisms involved in the induction of parturition in humans and other primates have been obscure, but recent studies in the rhesus monkey suggest androgens produced by the fetal adrenals play a central role. Infusion of androgen into either the pregnant rhesus maternal or fetal circulation increased estrogen production during late pregnancy and induced uterine contractions that were indistinguishable from those during normal parturition (3). Increased estrogen drives both connexin-43 and oxytocin receptor expression in the myometrium, key aspects of normal primate parturition and particularly important for the onset of organized, coordinated contractions. Increasing estrogen has also been proposed to promote NAD+-dependent 11ß-hydroxysteroid dehydrogenase activity in the placenta, reducing fetal plasma cortisol concentrations and activating the fetal hypothalamic-pituitary-adrenal axis, an important prerequisite for fetal lung maturation (2). These and other estrogen-dependent events form an important component of parturition in higher primates, including the human. DHEA-S is an obligate precursor of placental estrogen production in higher primates in which the placenta lacks the P450c17 enzyme activity required for de novo synthesis of estrogen from cholesterol.

Our data suggest a novel mechanism by which an increase in CRH production by the placenta might precipitate parturition. Specifically, placental CRH secreted into the fetal circulation may stimulate the synthesis of DHEA-S by the fetal adrenal, leading to increased estrogen concentrations and parturition (see Fig. 4Go). The effect of CRH on the adrenal is mediated via CRH receptors on fetal zone cells. Based on our Northern blot analyses, this CRH receptor is similar or identical to the type-1 receptor previously identified in the pituitary. Activation of the CRH receptor leads to increased expression of the steroid biosynthetic enzymes required for DHEA-S synthesis, i.e. P450scc and P450c17. The DHEA-S so-produced would then drive parturition, through its subsequent conversion to estrogen, as previously suggested by Mecenas et al. (3).



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  		Figure 4. Schematic model of the likely mechanism of action of CRH in coordinating the timing of human parturition. An increase in bioactive placental CRH at term has effects on both the fetus and the mother. In the fetus, CRH stimulates the fetal adrenal directly, to stimulate production of DHEA-S, which is converted by the placenta to estrogen, which in turn, drives expression of oxytocin receptors and connexin-43 for the formation of gap junctions in the maternal myometrium, events necessary for successful uterine contractions and parturition. The placental CRH may also act on the fetal adrenal cortex indirectly, by stimulating fetal pituitary production of ACTH, which evokes fetal adrenal cortisol production from the definitive zone and DHEA-S production from the fetal zone. A feed-forward loop, proposed by Robinson et al. (2 29 ), is thus started, as fetal adrenal cortisol production, in turn, stimulates CRH production by the placenta. This mechanism would ensure that maturation of the fetus (by cortisol) was coordinated with the progression of parturition (determined by DHEA-S production). In the mother, the high concentrations of placental CRH uncouple the CRH receptor in the myometrium from adenylate cyclase, leading to a fall in cAMP production and, consequently, removal of relaxant effects (26 ), so that uterotonic agents (such as oxytocin) prevail, and labor can successfully occur. CRH may also synergize with oxytocin and PG in promoting myometrial contractions for successful parturition (27 28 ).

 
For placental CRH to drive fetal DHEA-S production, adequate CRH concentrations must be released into the fetal circulation. Data on human fetal CRH concentrations are limited because of the ethical constraints related to fetal sampling. Most data relate to term umbilical cord concentrations, which generally are reported to be 10-fold lower than maternal concentrations but still 100-fold higher than those in nonpregnant adults (30). The CRH concentrations in the fetal circulation during pregnancy, therefore, remain uncertain; however, reasonable estimates based on umbilical sampling at 16–24 weeks suggest mean concentrations of 0.7 pmol/L in the fetus vs. 1.6 pmol/L in the mother, increasing to 31 pmol/L at term (31, 32). These concentrations are within the range observed to have activity on cultured fetal adrenal zone cells. Thus, placental CRH could be exerting an effect on fetal adrenal DHEA-S production, at least by 16 weeks of gestation. A further potential influence is the circulating binding protein for CRH (CRH-BP). CRH-BP circulates in human maternal and fetal plasma but not in the plasma of lower primates and other mammals (33, 34). The CRH-BP has been suggested to modify the bioavailability of CRH (33); however, CRH-BP concentrations remain stable in the maternal circulation until the last weeks of pregnancy, when a fall occurs. CRH-BP has been demonstrated in the fetal circulation (34), but detailed studies on gestational changes have not been reported. Our results do not indicate a major effect of CRH on fetal adrenal growth, and it seems likely, from previous studies of anencephalic fetuses, that fetal pituitary-derived factors, such as ACTH, are crucial for the development of the fetal zone. ACTH also is effective in stimulating DHEA-S secretion from cultured adrenal fetal zone cells at concentrations found in the fetal circulation [18–54 pmol/L (35, 36)]. The precise interactions between CRH and other local and systemic factors remain unknown; nevertheless, it seems likely that placental production of CRH plays an important role in coordinating the progressive increase in estrogen production during pregnancy and ensuring that fetal maturation and the processes of parturition are congruent. Our data suggest that placental CRH secretion into the fetal circulation is an important component of primate (and particularly human) parturition, driving fetal zone secretion of DHEA-S.


   Footnotes
 
1 This work was supported, in part, by NIH Grants HD-08478 and HD-11729 and by the Australian National Health and Medical Research Council. Back

Received January 6, 1998.

Revised April 20, 1998.

Accepted May 5, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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